Hemoglobin's α‐Helix‐to‐β‐Sheet Transition Enables Targeted mRNA Delivery to the Lung

Effective treatment of pulmonary diseases remains constrained by the scarcity of delivery systems capable of selective tissue targeting. Herein, we report a lung-targeting platform created through the structural repurposing of hemoglobin (Hb). Acidic heating enables a conformational shift of Hb from α-helix to β-sheet, leading to its self-assembly into fibrils (HbFs). Unexpectedly, intravenously injected HbFs exhibit rapid and specific accumulation in the lungs. Cryo-electron microscopy (cryo-EM) structure determination revealed a fibril surface rich in positively charged residues, which facilitates two key functions: selective binding to circulating platelets via a hitchhiking mechanism for lung targeting, and efficient electrostatic complexation with mRNA. In a therapeutic application, HbFs loaded with mRNA encoding an interleukin-11 single-chain fragment variable (IL-11 scFv) were administered in a murine model of bleomycin-induced pulmonary fibrosis. The formulation achieved lung-specific delivery with predominant uptake by pulmonary fibroblasts, enabling sustained local IL-11 scFv expression. Consequently, treatment significantly suppressed fibroblast activation and migration, attenuated collagen deposition, restored lung function. This work establishes HbFs as a novel protein‑based vehicle for targeted mRNA delivery, leveraging natural cellular trafficking pathways to enable localized therapy for lung disorders.